Lesinurad

Indications

Lesinurad is used for: Hyperuricemia, Indicated in combination with a xanthine oxidase inhibitor for hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone

Adult Dose

Oral Tablet Hyperuricemia Indicated in combination with a xanthine oxidase inhibitor for hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone 200 mg PO once daily in combination with a xanthine oxidase inhibitor (ie, allopurinol or febuxostat) Not to exceed 200 mg/day Not recommended for the treatment of asymptomatic hyperuricemia Do not use as monotherapy; failure to take lesinurad with a xanthine oxidase inhibitor may increase the risk of renal adverse reactions Hepatic impairment: Not recommended for patients with severe hepatic impairment.

Child Dose

<18 years: Safety and efficacy not established

Renal Dose

Renal impairment CrCl ?45 mL/min: No dosage adjustment required CrCl <45 mL/min: Do not initiate lesinurad Discontinue lesinurad if estimated CrCl is persistently <45 mL/min

Administration

Coadminister with a xanthine oxidase inhibitor Not recommended for patients taking allopurinol <300 mg/day (or <200 mg/day if estimated CrCl <60 mL/min) Take at the same time as the morning dose of xanthine oxidase inhibitor If treatment with the xanthine oxidase inhibitor is interrupted, lesinurad should also be interrupted Patients should be instructed to stay well hydrated (eg, 2 liters [68 oz] of liquid per day) Failure to follow these instructions may increase the risk of renal events

Contra Indications

Severe renal impairment (estimated CrCl <30 mL/min), end-stage renal disease, kidney transplant recipients, or patients on dialysis Tumor lysis syndrome or Lesch-Nyhan syndrome

Precautions

Acute renal failure has occurred and was more common when lesinurad was given alone Should be used in combination with a xanthine oxidase inhibitor Adverse effects related to renal function have occurred after initiating lesinurad; incidence was higher with doses exceeding 200 mg/day, with the highest incidence occurring with monotherapy use; monitor renal function at initiation and during therapy, particularly in patients with estimated CrCl <60 mL/min, and evaluate for signs and symptoms of acute uric acid nephropathy Major adverse cardiovascular events were observed during clinical trials (defined as cardiovascular deaths, nonfatal myocardial infarctions, or nonfatal strokes); a causal relationship has not been established Lactation Unknown if distributed in human breast milk It is present in the milk of rats

Pregnancy-Lactation

Pregnancy There are no available human data on use in pregnant women to inform a drug-associated risk Animal data No teratogenicity or effects on fetal development were observed in embryo-fetal development studies with oral administration of lesinurad to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to approximately 45 and 10 times, respectively, the exposure at the maximum recommended human dose (MRHD) No adverse developmental effects were observed in a prenatal and postnatal development study with administration of lesinurad to pregnant rats from organogenesis through lactation at a dose approximately 5 times the MRHD Lactation Unknown if distributed in human breast milk It is present in the milk of rats Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Interactions

Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when lesinurad is coadministered; use additional methods of nonhormonal contraception Doses of aspirin >325 mg/day may decrease lesinurad efficacy Lesinurad is a CYP2C9 substrate and its exposure is increased when coadministered with CYP2C9 inhibitors and in CYP2C9 poor metabolizers, while its exposure is decreased when coadministered with CYP2C9 inducers caution with sensitive CYP3A substrates

Side Effects

Side effects of Lesinurad : 1-10% Headache (5.3%) Influenza (5.1%) GERD (2.7%) Renal failure (1.2%) Serum creatinine Increased creatinine (4.3%) Elevation 1.5 to <2 x baseline (3.9%) Elevation ≥2 x baseline (1.8%) Nearly 90% resolved by end of study <1% Nephrolithiasis

Mode of Action

Selective uric acid reabsorption inhibitor (SURI); it acts by inhibiting the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid It also inhibits organic anion transporter 4 (OAT4), a uric acid transporter associated with diuretic-induced hyperuricemia